Growth hormone (GH), which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects of the metabolic processes of the body:
1. Increased rate of protein synthesis in substantially all cells of the body; PA1 2. Decreased rate of carbohydrate utilization in cells of the body; and PA1 3. Increased mobilization of free fatty acids and use of fatty acids for energy. PA1 --NR.sup.2 --C(O)--NR.sup.2 --, PA1 --NR.sup.2 --S(O).sub.2 --NR.sup.2 --, PA1 --O--C(O)--NR.sup.2 --, PA1 --NR.sup.2 --C(O)--O--, PA1 --C(O)--NR.sup.2 --C(O)--, PA1 --C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --S(O).sub.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--O--C(O)--, PA1 --C(R.sup.9 R.sup.10)--O--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --C(O)--C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(O)--NR.sup.2 --, PA1 --C(O)--NR.sup.2 --C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(O)--O--, PA1 --C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--O--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9.sup.10)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --S(O).sub.2 --NR.sup.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--O--C(O)--, PA1 --NR.sup.2 --C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --S(O).sub.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--NR.sup.2 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--O--, PA1 --C(R.sup.9 R.sup.10)--O--C(O)--NR.sup.2, PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--NR.sup.2 --, PA1 --NR.sup.2 --C(O)--O--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --S(O).sub.2 --NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --C(O)--N.dbd.C(R.sup.11)--NR.sup.2 --, PA1 --C(O)--NR.sup.2 --C(R.sup.11).dbd.N--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.12 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.12 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.12 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--O--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --C(R.sup.11).dbd.N--C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--N(R.sup.12)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.12 --, PA1 --N.dbd.C(R.sup.11)--NR.sup.2 --C(O)--, PA1 C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--NR.sup.2 --S(O).sub.2 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--S(O).sub.2 --NR.sup.2 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--O--, PA1 --C(R.sup.9 R.sup.10)--S(O).sub.2 --C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--S(O).sub.2 --, PA1 --O--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--O--, PA1 --C(R.sup.9 R.sup.10)--C(O)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)-- and PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --S(O).sub.2 --NR.sup.2 --; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; PA1 Y.sup.1 is O, S(O).sub.m, --C(O)NX.sup.6 --, --CH.dbd.CH--, --C.ident.C--, --N(X.sup.6)C(O)--, --C(O)NX.sup.6 --, --C(O)O--, --OC(O)N(X.sup.6)--or --OC(O)--; PA1 q is 0, 1, 2, 3 or 4; PA1 t is 0, 1, 2 or 3; PA1 said (CH.sub.2).sub.q group and (CH.sub.2).sub.t group in the definition of R.sup.1 are optionally independently substituted with hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups of 1 or 2 (C.sub.1 -C.sub.4)alkyl groups; PA1 where the alkyl groups and the cycloalkyl groups in the definition of R.sup.2 are optionally substituted with hydroxy, --C(O)OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --(X.sup.6)(X.sup.6), --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)A.sup.1, --C(O)(X.sup.6), CF.sub.3, CN or 1, 2 or 3 independently selected halo groups; PA1 where the alkyl groups in the definition of R.sup.3 are optionally substituted with --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)OX.sup.3, 1, 2, 3, 4 and 5 independently selected halo groups of 1, 2 or 3 independently selected --OX.sup.3 groups; PA1 X.sup.1 is O, S(O).sub.m, --N(X.sup.2)C(O)--, --C(O)N(X.sup.2)--, --OC(O)--, --C(O)O--, --CX.sup.2.dbd.CX.sup.2 --, --N(X.sup.2)C(O)O--, --OC(O)N(X.sup.2)--or --C.ident.C--; PA1 where a and b are each independently 0, 1, 2 or 3; PA1 X.sup.5 and X.sup.5a are each independently selected from the group consisting of hydrogen, CF.sub.3, A.sup.1 and optionally substituted (C.sub.1 -C.sub.6)alkyl; PA1 or the carbon bearing X.sup.5 or X.sup.5a forms one or two alkylene bridges with the nitrogen atom bearing R.sup.7 and R.sup.8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then only one of X.sup.5 or X.sup.5a is on the carbon atom and only one of R.sup.7 or R.sup.8 is on the nitrogen atom and further provided that when two alkylene bridges are formed then X.sup.5 and X.sup.5a cannot be on the carbon atom and R.sup.7 and R.sup.8 cannot be on the nitrogen atom; PA1 or X.sup.5 is taken together with X.sup.5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; PA1 or X.sup.5 is taken together with X.sup.5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5-or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated of fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; PA1 Z.sup.1 is a bond, O or N--X.sup.2, provided that when a and b are both 0 then Z.sup.1 is not N--X.sup.2 or O; PA1 where the optionally substituted (C.sub.1 -C.sub.6)alkyl in the definition of R.sup.7 and R.sup.8 is optionally independently substituted with A.sup.1, --C(O)O--(C.sub.1 -C.sub.6)alkyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 --O--C(O)(C.sub.1 -C.sub.10)alkyl groups or 1 to 3 (C.sub.1 -C.sub.6)alkoxy groups; or PA1 where L is C(X.sup.2)(X.sup.2), S(O).sub.m or N(X.sup.2); PA1 A.sup.1 for each occurrence is independently optionally substituted, on one or optionally both rings if A.sup.1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF.sub.3, OCF.sub.2 H, CF.sub.3, CH.sub.3, OCH.sub.3, --OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --C(O)OX.sup.6, oxo, (C.sub.1 -C.sub.6)alkyl, nitro, cyano, benzyl, --S(O).sub.m (C.sub.1 -C.sub.6 (alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, --N(X.sup.6)(X.sup.6), --N(X.sup.6 (C(O)(X.sup.6), --S(O).sub.2 N(X.sup.6)(X.sup.6), --N(X.sup.6 (S(O).sub.2 -phenyl, --N(X.sup.6)S(O).sub.2 X.sup.6, --CONX.sup.11 X.sup.12, --S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 X.sup.12, --NX.sup.6 CONX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 C(O)X.sup.12, imidazolyl, thiazolyl and tetrazolyl, provided that if A.sup.1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; PA1 X.sup.7 is hydrogen or (C.sub.1 -C.sub.6)alkyl optionally substituted with hydroxy; PA1 X.sup.6 and X.sup.12 cannot be hydrogen when attached to C(O) or S(O).sub.2 in the form C(O)X.sup.6, C(O)X.sup.12, S(O).sub.2 X.sup.6 or S(O).sub.2 X.sup.12, and PA1 when R.sup.6 is a bond then L is N(X.sup.2) and each r in the definition --(CH.sub.2).sub.1 --L--(CH.sub.2).sub.1 -- is independently 2 or 3. PA1 where the optionally substituted (C.sub.1 -C.sub.6)alkyl in the definition of X.sup.5 and X.sup.5a is optionally substituted with OX.sup.2 or A.sup.1 ; PA1 where the aryl portion(s) of the groups defined for R.sup.3 are each optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3, OCF.sub.2 H and CF.sub.3. PA1 where the aryl portion(s) of the groups defined for R.sup.3 are each optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of methylenedioxy, F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.3, OCF.sub.2 H, and CF.sub.3. PA1 A.sup.1 in the definition of R.sup.1 is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1 to 3 fluoro atoms; PA1 q is 1 or 2; t is 1 or 2; PA1 where the aryl portion of the groups defined for R.sup.3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; and PA1 R.sup.2 is hydrogen, (C.sub.1 -C.sub.5)alkyl or --(C.sub.0 -C.sub.2)alkyl-(C.sub.3 -C.sub.8)cycloalkyl; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1, 2 or 3 fluoro groups. PA1 R.sup.2 is hydrogen, (C.sub.1 -C.sub.5)alkyl or --(C.sub.0 -C.sub.2)alkyl-(C.sub.3 -C.sub.8)cycloalkyl; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1,2 or 3 fluoro groups. PA1 R.sup.2 is hydrogen, (C.sub.1 -C.sub.5)alkyl or --(C.sub.0 -C.sub.2)alkyl-(C.sub.3 -C.sub.8)cycloalkyl; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1, 2 or 3 fluoro groups. PA1 R.sup.2 is methyl or ethyl where the ethyl group is optionally substituted with 1-3 fluoro groups; and PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1, 2 or 3 fluoro groups; PA1 A.sup.1 in the definition of R.sup.1 is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1 to 3 fluoro groups; t is 1 or 2; q is 1 or 2; and PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1, 2 or 3 fluoro groups. PA1 A.sup.1 in the definition of R.sup.1 is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1-3 fluoro groups; t is 1 or 2; q is 1 or 2; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1-3 fluoro groups. PA1 A.sup.1 in the definition of R.sup.1 is phenyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1-3 fluoro groups; t is 1 or 2; q is 1 or 2; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1-3 fluoro groups. PA1 A.sup.1 in the definition of R.sup.1 is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1-3 fluoro groups; PA1 t is 1 or 2; q is 1 or 2; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1-3 fluoro groups; PA1 R.sup.2 is hydrogen, (C.sub.1 -C.sub.5)alkyl or --(C.sub.0 -C.sub.2)alkyl-(C.sub.3 -C.sub.8)cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R.sup.2 are optionally substituted with 1, 2 or 3 fluoro groups; PA1 methods for increasing levels of endogenous growth hormone in a human or other animal such as especially dogs, cats and horses, which comprise administering to such human or other animal an effective amount of a compound of Formula I; PA1 pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and an effective amount of a compound of Formula I; PA1 pharmaceutical compositions useful for increasing the endogenous production or release of growth hormone in a human or other animal which comprise a pharmaceutically acceptable carrier, an effective amount of a compound of Formula I and a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof; PA1 methods for treating or preventing osteoporosis and/or frailty which comprise administering to a human or other animal especially dogs, cats and horses, in need of such treatment or prevention an amount of a compound of Formula I which is effective in treating or preventing osteoporosis and/or frailty; PA1 methods for treating or preventing diseases or conditions which may be treated or prevented by growth hormone which comprise administering to a human or other animal in need of such treatment or prevention an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; PA1 preferred methods of the immediately foregoing methods is where the disease or condition is congestive heart failure, frailty associated with aging or obesity; PA1 preferred methods of the immediately foregoing methods is where the disease or condition is congestive heart failure or frailty associated with aging; PA1 methods for accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness such as AIDS or cancer, accelerating would healing, or accelerating the recovery of burn patients or patients having undergone major surgery, which methods comprise administering to a mammal in need of such treatment an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; PA1 preferred methods of the immediately foregoing methods is for accelerating the recovery of patients having undergone major surgery or for accelerating bone fracture repair; PA1 methods for improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis, which methods comprise administering to a human or other animal in need of such treatment an amount of a compound of Formula I which is effective in promoting release of endogenous growth hormone; PA1 methods for the treatment or prevention of osteoporosis and/or frailty which comprises administering to a human or other animal especially dogs, cats and horses, with osteoporosis and/or frailty effective amounts of a bisphosphonate compound and a compound of Formula I; PA1 preferred methods of the immediately foregoing methods is where the bisphosphonate compound is alendronate or ibandronate; PA1 methods for the treatment or prevention of osteoporosis and/or frailty which comprise administering to a human or other animal especially dogs, cats and horses, with osteoporosis and/or frailty effective amounts of estrogen or Premarin.RTM. and a compound of Formula I and, optionally, progesterone; PA1 methods for the treatment of osteoporosis and/or frailty which comprise administering to a human or other animal especially dogs, cats and horses, with osteoporosis and/or frailty effective amounts of calcitonin and a compound of Formula I; PA1 methods to increase IGF-1 levels in a human or other animal especially dogs, cats and horses, deficient in IGF-1 which comprise administering to a human or other animal with IGF-1 deficiency a compound of Formula I; PA1 methods for the treatment of osteoporosis and/or frailty which comprises administering to a human or other animal especially dogs, cats and horses, with osteoporosis and/or frailty effective amounts of an estrogen agonist or antagonist and a compound of Formula I; PA1 preferred methods of the immediately foregoing methods is where the estrogen agonist or antagonist is tamoxifen, droloxifene, raloxifene, idoxifene, cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tet rahydro-naphthalene-2-ol; (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydr o-naphthalene-2-ol; cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-na phthalene-2-ol; cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahy dro-naphthalene; 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetra hydroisoquinoline; cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tet rahydro-naphthalene-2-ol; or 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydro-isoq uinoline. PA1 methods for enhancing growth and improving carcass quality of an animal other than humans which comprise administering to said animal an effective amount of a compound of Formula I; PA1 methods for enhancing feed efficiency in an animal other than humans which comprise administering to said animal an effective amount of a compound of Formula I; PA1 methods for increasing milk production in a female mammal which comprise administering to said female mammal an effective amount of a compound of Formula I; PA1 methods for increasing piglet number, increasing pregnancy rate in sows, increasing viability of piglets, increasing weight of piglets or increasing muscle fiber size in piglets which comprise administering to a sow or piglet an effective amount of a compound of Formula I; PA1 methods for increasing muscle mass, which comprise administering to a human or other animal such as dogs, cats, horses, cattle, pigs, chickens, turkeys, sheep and fish, in need of such treatment an amount of a compound of Formula I; PA1 methods for promoting growth in growth hormone deficient children which comprise administering to a growth hormone deficient child a compound of Formula I; PA1 methods for the treatment or prevention of congestive heart failure, obesity or frailty associated with aging, which comprise administering to a human or other animal in need thereof effective amounts of a functional somatostatin antagonist and a compound of Formula I; PA1 preferred methods of the immediately foregoing methods is where the functional somatostatin antagonist is an alpha-2 adrenergic agonist and the other animal is a dog, cat or a horse; PA1 preferred methods of the immediately foregoing methods is where the alpha-2 adrenergic agonist is clonidine, xylazine or medetomidine. PA1 methods for treating insulin resistance in a mammal, which comprises administering to said mammal an effective amount of a compound of Formula I; PA1 preferred methods of the immediately foregoing methods is where the condition associated with insulin resistance is type I diabetes, type II diabetes, hyperglycemia, impaired glucose tolerance or an insulin resistant syndrome; or where the condition associated with insulin resistance is associated with obesity or old age; PA1 methods for increasing the endogenous production or release of growth hormone in a human or other animal especially dogs, cats and horses, which comprise administering effective amounts of a compound of Formula I and a growth hormone secretagogue selected from the group consisting of GHRP-6, Hexarelin, GHRP-1, growth hormone releasing factor (GRF), IGF-1, IGF-2 and B-HT920 or an analog thereof; PA1 pharmaceutical compositions useful for treating or preventing osteoporosis and/or frailty which comprise a pharmaceutically acceptable carrier, an amount of a bisphosphonate compound and an amount of a compound of Formula I; PA1 pharmaceutical compositions useful for treating or preventing osteoporosis and/or frailty which comprises a pharmaceutically acceptable carrier, an amount of estrogen or Premarin.RTM., an amount of a compound of Formula I and, optionally, an amount of progesterone; PA1 pharmaceutical compositions useful for treating osteoporosis and/or frailty which comprise a pharmaceutically acceptable carrier, an amount of calcitonin and an amount of a compound of Formula I; PA1 pharmaceutical compositions useful for treating preventing congestive heart failure, obesity or frailty associated with aging, which comprise a pharmaceutically acceptable carrier, an amount of an alpha-2 adrenergic agonist and an amount of a compound of Formula I; PA1 a preferred pharmaceutical composition of the immediately foregoing compositions is where the alpha-2 adrenergic agonist is clonidine, xylazine or medetomidine; and PA1 methods for increasing levels of endogenous growth hormone, which comprise administering to a human or other animal in need thereof effective amounts of a functional somatostatin antagonist and a compound of Formula I. PA1 where R.sup.9 in the definition of Y is selected from the group consisting of hydrogen, fluoro, hydroxy and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups; and R.sup.10 in the definition of Y is selected from the group consisting of hydrogen, fluoro, and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups with the proviso that R.sup.10 cannot be fluoro when R.sup.9 is hydroxy; PA1 where R.sup.9 in the definition of X is selected from the group consisting of hydrogen, fluoro, hydroxy and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups. PA1 where R.sup.9 and R.sup.10 in the definition of Y are independently selected from the group consisting of hydrogen, fluoro, and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups. PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --S(O).sub.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--O--C(O)--, PA1 --C(R.sup.9 R.sup.10)--O--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --C(O)--C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(O)--NR.sup.2 --, PA1 --C(R.sup.9 R.sup.10)--C(O)--O--, PA1 --C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--O--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --S(O).sub.2 --NR.sup.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--O--C(O)--, PA1 NR.sup.2 --C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --S(O).sub.2 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--NR.sup.2, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--O--, PA1 --C(R.sup.9 R.sup.10)--O--C(O)--NR.sup.2, PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --C(O)--NR.sup.2 --, PA1 --NR.sup.2 --C(O)--O--C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.2 --S(O).sub.2 --NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --O--C(O)--NR.sup.2 --C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.12 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.12 --C(R.sup.9 R.sup.10)--, PA1 --NR.sup.12 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--O--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--N(R.sup.12)--, PA1 --C(R.sup.9 R.sup.10)--NR.sup.12 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--NR.sup.2 --S(O).sub.2 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--S(O).sub.2 --NR.sup.2 --, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--C(O)--O--, PA1 --C(R.sup.9 R.sup.10)--S(O).sub.2 --C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--S(O).sub.2 --, PA1 --O--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--, PA1 --C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)--O--, PA1 --C(R.sup.9 R.sup.10)--C(O)--C(R.sup.9 R.sup.10)--, PA1 --C(O)--C(R.sup.9 R.sup.10)--C(R.sup.9 R.sup.10)-- and PA1 --C(R.sup.9 R.sup.10)--NR.sup.2 --S(O).sub.2 --NR.sup.2 --; PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; PA1 Y.sup.1 is O, S(O).sub.m, --C(O)NX.sup.6 --, --CH.dbd.CH--, --C.ident.C--, --N(X.sup.6)C(O)--, --C(O)NX.sup.6 --, --C(O)O--, --OC(O)N(X.sup.6)-- or --OC(O)-; PA1 q is 0, 1, 2, 3 or 4; PA1 t is 0, 1, 2 or 3; PA1 said (CH.sub.2).sub.q group and (CH.sub.2).sub.t group in the definition of R.sup.1 are optionally independently substituted with hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C.sub.1 -C.sub.4)alkyl groups; PA1 where the alkyl groups and the cycloalkyl groups in the definition of R.sup.2 are optionally substituted with hydroxy, --C(O)OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --N(X.sup.6)(X.sup.6), --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)A.sup.1, --C(O)(X.sup.6), CF.sub.3, CN or 1, 2 or 3 independently selected halo groups; PA1 where the alkyl groups in the definition of R.sup.3 are optionally substituted with --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --C(O)OX.sup.3, 1, 2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected --OX.sup.3 groups; PA1 X.sup.1 is O, S(O).sub.m, --N(X.sup.2)C(O)--, --C(O)N(X.sup.2)--, --OC(O)--, --C(O)O--, --CX.sup.2.dbd.CX.sup.2 --, --N(X.sup.2)C(O)O--, --OC(O)N(X.sup.2)-- or --C.ident.C--; PA1 where a and b are each independently 0, 1, 2 or 3; PA1 X.sup.5 and X.sup.5a are each independently selected from the group consisting of hydrogen, CF.sub.3, A.sup.1 and optionally substituted (C.sub.1 -C.sub.6)alkyl; PA1 or the carbon bearing X.sup.5 or X.sup.5a forms one or two alkylene bridges with the nitrogen atom bearing R.sup.7 and R.sup.8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then only one of X.sup.5 or X.sup.5a is on the carbon atom and only one of R.sup.7 or R.sup.8 is on the nitrogen atom and further provided that when two alkylene bridges are formed then X.sup.5 and X.sup.5a cannot be on the carbon atom and R.sup.7 and R.sup.8 cannot be on the nitrogen atom; PA1 or X.sup.5 is taken together with X.sup.5a and the carbon atoms to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; PA1 or X.sup.5 is taken together with X.sup.5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; PA1 Z.sup.1 is a bond, O or N--X.sup.2, provided that when a and b are both 0 then Z.sup.1 is not N--X.sup.2 or O; PA1 where the optionally substituted (C.sub.1 -C.sub.6)alkyl in the definition of R.sup.7 and R.sup.8 is optionally independently substituted with A.sup.1, --C(O)O-(C.sub.1 -C.sub.6)alkyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 --O--C(O)(C.sub.1 -C.sub.10)alkyl groups or 1 to 3 (C.sub.1 -C.sub.6)alkoxy groups; or PA1 where L is C(X.sup.2)(X.sup.2), S(O).sub.m or N(X.sup.2); PA1 A.sup.1 for each occurrence is independently optionally substituted, on one or optionally both rings if A.sup.1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, l, OCF.sub.3, OCF.sub.2 H, CF.sub.3, CH.sub.3, OCH.sub.3, --OX.sup.6, --C(O)N(X.sup.6)(X.sup.6), --C(O)OX.sup.6, oxo, (C.sub.1 -C.sub.6)alkyl, nitro, cyano, benzyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, --N(X.sup.6)(X.sup.6), --N(X.sup.6)C(O)(X.sup.6), --S(O).sub.2 N(X.sup.6)(X.sup.6), --N(X.sup.6)S(O).sub.2 -phenyl, --N(X.sup.6)S(O).sub.2 X.sup.6, --CONX.sup.11 X.sup.12, --S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 X.sup.12, --NX.sup.6 CONX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 C(O)X.sup.12, imidazolyl, thiazolyl and tetrazolyl, provided that if A.sup.1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; PA1 X.sup.7 is hydrogen or (C.sub.1 -C.sub.6)alkyl optionally substituted with hydroxy; PA1 X.sup.6 and X.sup.12 cannot be hydrogen when attached to C(O) or S(O).sub.2 in the form C(O)X.sup.6, C(O)X.sup.12, S(O).sub.2 X.sup.6 or S(O).sub.2 X.sup.12 ; and PA1 when R.sup.6 is a bond then L is N(X.sup.2) and each r in the definition --(CH.sub.2).sub.r --L--(CH.sub.2).sub.r -- is independently 2 or 3. PA1 where A.sup.1 in the definition or R.sup.1 is phenyl, pyridyl, thiazolyl or thienyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 ; PA1 the cycloalkyl and alkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy or 1 to 3 fluoro atoms; PA1 q is 1 or 2; PA1 t is 1 or 2; PA1 where the aryl portion of the groups defined for R.sup.3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3 PA1 where R.sup.9 in the definition of Y is selected from the group consisting of hydrogen, fluoro, hydroxy, (C.sub.1 -C.sub.2)alkoxy and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups; and R.sup.10 in the definition of Y is selected from the group consisting of hydrogen, fluoro, and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups with the proviso that R.sup.10 cannot be fluoro when R.sup.9 is hydroxy or (C.sub.1 -C.sub.2)alkoxy; PA1 where R.sup.9 in the definition of X is selected from the group consisting of hydrogen, fluoro, hydroxy, (C.sub.1 -C.sub.2)alkoxy and (C.sub.1 -C.sub.2)alkyl optionally substituted with 1-3 fluoro groups. PA1 where A.sup.1 is phenyl, pyridyl or thiazolyl, optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, PCF.sub.2 H, OCF.sub.3 ; and PA1 where the aryl portion of the groups defined for R.sup.3 is optionally substituted with one to three substituents, each substituent being independently selected from the group consisting of F, Cl, CH.sub.3, OCH.sub.3, OCF.sub.2 H, OCF.sub.3 and CF.sub.3. PA1 where the alkyl and cycloalkyl groups in the definition of R.sup.1 are optionally substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; PA1 Y.sup.1 is O, S(O).sub.m, --C(O)NX.sup.6 --, --CH.dbd.CH--, --C.ident.C--, --N(X.sup.6)C(O)--, --C(O)NX.sup.6 --, --C(O)O--, --OC(O)N(X.sup.6)-- or --OC(O)--; PA1 m for each occurrence is 0, 1 or 2; PA1 q is 0, 1, 3, 3 or 4; PA1 t is 0, 1, 2 or 3; PA1 said (CH.sub.2).sub.q group and (CH.sub.2).sub.t group in the definition of R.sup.1 are optionally independently substituted with hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, --CONH.sub.2, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, --CO.sub.2 (C.sub.1 -C.sub.4)alkyl ester, 1H-tetrazol-5-yl, 1 2 or 3 fluoro groups or 1 or 2 (C.sub.1 -C.sub.4)alkyl groups; PA1 A.sup.1 for each occurrence is independently optionally substituted, on one or optionally both rings if A.sup.1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF.sub.3, OCF.sub.2 H, CF.sub.3, CH.sub.3, OCH.sub.3, --OX.sup.5, --C(O)N(X.sup.6)(X.sup.6), --C(O)OX.sup.6, oxo, (C.sub.1 -C.sub.6)alkyl, nitro, cyano, benzyl, --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, 1H-tetrazol-5yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, --N(X.sup.6)(X.sup.6), --N(X.sup.6)C(O)(X.sup.6) --S(O).sub.2 N(X.sup.6)(X.sup.6), --N(X.sup.6)S(O).sub.2 -phenyl, --N(X.sup.6)S(O).sub.2 X.sup.6, --CONX.sup.11 X.sup.12, --S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 X.sup.12, --NX.sup.6 CONX.sup.11 X.sup.12, --NX.sup.6 S(O).sub.2 NX.sup.11 X.sup.12, --NX.sup.6 C(O)X.sup.12, imidazolyl, thiazolyl and tetrazolyl, provided that if A.sup.1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; PA1 L.sup.1 is C(X.sup.2)(X.sup.2), O, S(O).sub.m or N(X.sup.2); PA1 X.sup.6 for each occurrence is independently hydrogen, optionally substituted (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)halogenated alkyl, optionally substituted (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.3 -C.sub.7)-halogenated cycloalkyl, where optionally substituted (C.sub.1 -C.sub.6)alkyl and optionally substituted (C.sub.3 -C.sub.7)cycloalkyl in the definition of X.sup.6 is optionally independently mono- or di-substituted with (C.sub.1 -C.sub.4)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkoxy, carboxyl, CONH.sub.2, PA1 --S(O).sub.m (C.sub.1 -C.sub.6)alkyl, carboxylate (C.sub.1 -C.sub.4)alkyl ester or 1H-tetrazol-5-yl; or when there are two X.sup.6 groups on one atom and both X.sup.6 are independently (C.sub.1 -C.sub.6)alkyl, the two (C.sub.1 -C.sub.6)alkyl groups may be optionally joined and, together with the atom to which the two X.sup.6 groups are attached, form a 4- to 9- membered ring optionally having oxygen, sulfur or NX.sup.7 as a ring member; and PA1 R.sup.2 is hydrogen, (C.sub.1 -C.sub.8)alkyl, --(C.sub.0 -C.sub.3)alkyl-(C.sub.3 -C.sub.6)cycloalkyl, --(C.sub.1 -C.sub.4)alkyl-A.sup.1 or A.sup.1 ; PA1 (a) reacting 8a-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-tetrahydro-imidazo[1,5-a]p yrazine-1,3-dione with D-tartaric acid in a reaction inert solvent to form 1,3-dioxo-8a-(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-im idazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester; PA1 (b) reacting said 1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imi dazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester with 3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methyl-propionylamino)-propion ic acid in the presence of a tertiary amine and 1-propanephosphonic acid cyclic anhydride in a reaction inert solvent to form (1-(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trif luoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)-1- methyl-ethyl)-carbamic acid tert-butyl ester; and PA1 (c) reacting said (1-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-tr ifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethylcarbamoyl)- 1-methyl-ethyl)-carbamic acid tert-butyl ester with concentrated hydrochloric acid in a reaction inert solvent to form 2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2 ,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-methyl-propio namide hydrochloride. PA1 --P(O)(OH).sub.2, --P(O)(O(C.sub.1 -C.sub.6)alkyl).sub.2 or glycosyl (the radical resulting from detachment of the hydroxyl of the hemiacetal of a carbohydrate). PA1 cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; PA1 (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro -naphthalene-2-ol; PA1 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-nap hthalene-2-ol; PA1 cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd ronaphthalene; PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-florophenyl)-6-hydroxy-1,2,3,4-tetrahy droisoquinoline; PA1 cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; and PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoquin oline. PA1 cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; PA1 (-)-cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro -naphthalene-2-ol; PA1 cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-nap hthalene-2-ol; PA1 cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd ronaphthalene; PA1 1-(4'-pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,3,4-tetrah ydroisoquinoline; PA1 cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetr ahydro-naphthalene-2-ol; or PA1 1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoqui noline is in the range of 0.0001 to 100 mg/kg/day, preferably 0.001 to 10 mg/kg/day. PA1 BOC t-Butyloxycarbonyl PA1 Bz Benzyl PA1 BOP Benzotriazol-1-yloxy tris(dimethylamino) phosphonium hexafluorophosphate PA1 CBZ Benzyloxycarbonyl PA1 CDI N,N'-Carbonyldiimidazole PA1 CDD Dicyclohexylcarbodiimide PA1 DEC 1,2-Diethylaminoethyl chloride hydrochloride PA1 DMAP 4-Dimethylaminopyridine PA1 DMF Dimethylformamide PA1 DPPA Diphenylphosphoryl azide PA1 ECD 1(3-Dimethylaminopropyl)-3-ethylcabodiimide hydrochloride PA1 EtOAc Ethyl acetate PA1 Hex Hexane PA1 HOAT 1-Hydroxy-7-azabenzotriazole PA1 HOBT Hydroxybenzotriazole hydrate PA1 HPLC High pressure liquid chromatography PA1 Hz Hertz PA1 KHMDS Potassium Bis(trimethylsilyl)amide PA1 LHMDS Lithium Bis(trimethylsilyl)amide PA1 MHz Megahertz PA1 MS Mass Spectrum PA1 NaHMDS Sodium Bis(trimethylsilyl)amide PA1 NMR Nuclear Magnetic Resonance PA1 PPAA 1-Propanephosphonic acid cyclic anhydride PA1 PTH Parathyroid hormone PA1 TFA Trifluoroacetic acid PA1 THF Tetrahydrofuran PA1 TLC Thin layer chromatography PA1 TRH Thyrotropin releasing hormone
Deficiency in growth hormone results in a variety of medical disorders. In children, it causes dwarfism. In adults, the consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced. Administration of exogenous growth hormone has been shown to reverse many of the metabolic changes. Additional benefits of therapy have included reduction in LDL cholesterol and improved psychological well-being.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in an expensive product, and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone (e.g., Jacob-Creutzfeld disease). Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or nasal spray.
Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of GH. Therefore, an alternative strategy for normalizing serum GH levels is by stimulating its release from somatotrophs. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion are being pursued, and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.
Physiologic and pharmacologic stimulators of GH secretion, which include arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the unknown secretagogue growth hormone releasing factor (GHRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
Obesity is a major risk factor for diabetes, and a large fraction of NIDDM patients are obese. Both conditions are characterized by elevated circulating insulin levels and suppressed GH levels. GH treatment of GH-deficient adults (Jorgensen, J. O. L., et al., Lancet 1:1221 (1989)), obese women (Richelsen, B., et al., Am J Physiol, 266:E211 (1994) and elderly men (Rudman, D., et al, Horm Res 36 (Suppl 1):73 (1991)) has been shown to produce increases in lean body, hepatic and muscle mass while decreasing fat mass. Thus, GH therapy for obesity would seem attractive except for the diabetogenic effects of GH.
An alternative to exogenous GH administration is therapy that stimulates endogenous GH secretion. It has been shown that a substantial pituitary reserve of GH is present in pituitary-intact GH-deficient patients and the elderly so that decreased serum GH levels are due to hyposecretion.
Hyposecretion of GH in several clinical settings (obesity, aging, glucocorticoid suppression) is relatively resistant to stimulation by GHRH (Gertz, B. J., et al., J Clin Endocrinol Metab, 79:745 (1994); Arvat, E., et al., J Clin Endocrinol Metab, 79:1440 (1994); Maccario, M., et al., Metabolism, 44:134 (1995)). In contrast, administration of a GHRP or combined administration of GHRH and a GHRP in these patients can elicit a robust GH response (Aloi, J. A., et al., J Clin Endocrinol Metab, 79:943; (1994)). Single dose studies of GHRPs have demonstrated the absence of an acute effect on circulating insulin or glucose levels. Insulin and glucose have generally not been monitored in chronic studies except to document the absence of unfavorable changes (Jacks, T., et al., J Endocrinol. 143:399 (1993)).
Prior to the present invention, the use of GHRPs or GHRP mimetics to improve glycemic control has not specifically been explored. The method of treating insulin resistance in a mammal comprising the administration of a compound of Formula I of this invention is practiced preferentially in patients who have a functional hypothalamic-pituitary axis capable of GH secretory responses to GHRPs and who have pancreatic beta-cells capable of secreting insulin.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones, are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low.
WO 94/13696 refers to certain spiropiperidines and homologues which promote release of growth hormone. Preferred compounds described therein are of the general structure shown below. ##STR2##
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure ##STR3##
where L is ##STR4##
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
PCT publication WO 97/09060 discloses the use of growth hormone releasing hormone or a functional analog thereof in the treatment of insulin resistance in mammals.